This is perhaps the best and most comprehensive transcriptome dataset of schizophrenia generated to date. It has multiple strengths, including the use of four different cortical regions, the correlation of genetics with transcriptomics, and the use of strong bioinformatics including WGCNA analysis. The findings are quite revealing. The results suggest that there is a strong, common signature across brain areas BA21, BA32, and BA38 that encompasses genes related to transcription/translation, signal transduction, the cell cycle, cell adhesion, the immune response, apoptosis, and the cytoskeleton.

Perhaps surprisingly, the expression signature was far less prominent in prefrontal cortical area BA 46, which is one of the most affected regions in schizophrenia. However, it was also clear that each brain region had a unique, region-specific schizophrenia signature. In addition, this study reproduced and validated a number of previously reported findings related to oligodendrocyte and mitochondrial transcript deficits. Nevertheless, the results of the current study disagree with the previously reported and replicated outcomes of similar assessments of other cohorts: in this study, GABA system genes were upregulated, and gene ontology categories related to immune response were downregulated in subjects with schizophrenia.

This is certainly noteworthy, and this apparent discrepancy in findings will have to be addressed by future experiments. I wish that the authors had addressed this issue in their discussion. The combined transcriptomics-genetics results suggest that the oligodendrocyte, GABA, and glutamate modules are (at least partially) driven by genetic vulnerability, while other gene expression changes might be secondary/adaptational in nature.

Finally, the study suggests that interregional coexpression is attenuated in schizophrenia. A very similar hypothesis, using WGCNA analysis of samples with autism, has been proposed in autism by the Geschwind laboratory (see Voineagu et al., 2011, and the commentary of Korade and Mirnics, 2011). Voineagu et al. reported that the differential patterns of gene expression that normally distinguish the frontal and temporal cortices are significantly attenuated in the autistic brain, potentially leading to loss of functional specifications across the affected cortical areas. This is certainly worth further exploration, and the schematic hypothesis presented in Figure 5 of the current paper is a logical blueprint that nicely maps out a possible sequence of pathophysiological events in schizophrenia. Still, the actual sequence of the proposed events can be debated at the current time: it is very likely that the cascades proposed by Figure 1 in the commentary by Korade et al. and Figure 5 in the current manuscript will have to be revised as our knowledge accumulates.